chr19-17337643-AA-GTG

Variant names:

• chr19-17337643-AA-GTG
• rs886037736
• NM_032620.4:c.32_33delAAinsGTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032620.4(GTPBP3):​c.32_33delAAinsGTG​(p.Gln11ArgfsTer98) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GTPBP3 NM_032620.4 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.788
• Publications: 0 publications found

Genes affected

GTPBP3 (HGNC:14880): (GTP binding protein 3, mitochondrial) This locus encodes a GTP-binding protein. The encoded protein is localized to the mitochondria and may play a role in mitochondrial tRNA modification. Polymorphisms at this locus may be associated with severity of aminoglycoside-induced deafness, a disease associated with a mutation in the 12S rRNA. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2010]

GTPBP3 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000307319 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17337643-AA-GTG is Pathogenic according to our data. Variant chr19-17337643-AA-GTG is described in ClinVar as Pathogenic. ClinVar VariationId is 180619.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP3	NM_032620.4	MANE Select	c.32_33delAAinsGTG	p.Gln11ArgfsTer98	frameshift missense	Exon 1 of 9	NP_116009.2
	GTPBP3	NM_133644.4		c.32_33delAAinsGTG	p.Gln11ArgfsTer98	frameshift missense	Exon 1 of 8	NP_598399.2
	GTPBP3	NM_001128855.3		c.32_33delAAinsGTG	p.Gln11ArgfsTer98	frameshift missense	Exon 1 of 9	NP_001122327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP3	ENST00000324894.13	TSL:1 MANE Select	c.32_33delAAinsGTG	p.Gln11ArgfsTer98	frameshift missense	Exon 1 of 9	ENSP00000313818.7
	GTPBP3	ENST00000600625.5	TSL:1	c.32_33delAAinsGTG	p.Gln11ArgfsTer98	frameshift missense	Exon 1 of 9	ENSP00000473150.1
	GTPBP3	ENST00000600610.5	TSL:1	n.32_33delAAinsGTG		non_coding_transcript_exon	Exon 1 of 7	ENSP00000469008.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation defect type 23 Pathogenic:1

Dec 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037736; hg19: chr19-17448452;